PROJECT SUMMARY Heart failure is the most common reason for adult hospitalization in the developed world. Therapies that target reversible causes of myocardial and peripheral organ dysfunction are likely to provide added benefit in heart failure with reduced ejection fraction (HFrEF). In addition, there are no proven effective pharmacologic therapies for heart failure with preserved ejection fraction (HFpEF), which accounts for ?50% of the heart failure burden. Triiodothyronine (T3), an endogenous thyroid hormone, exerts multiple effects on the cardiovascular system, mediated through T3 receptors in the myocardium and vasculature and directly on ion channels and mitochondria. Overarching effects of T3 include an increase in myocardial contractility and a decrease in systemic vascular resistance. Despite the high prevalence (~20-30%) of low T3 syndrome in heart failure, the exogenous administration of liothyronine (LT3), the synthetic form of T3, remains an underexplored therapeutic option. Low T3 syndrome has been associated with increased mortality in patients with HFrEF and disease severity in HFpEF, but whether it is a marker of poor health or a mediator of clinically relevant abnormalities in heart failure is unknown. Our overall goal is to determine the safety, feasibility, and preliminary efficacy of oral LT3 therapy in patients with HF and low T3. Proof of concept clinical studies using short-term intravenous LT3 infusions have demonstrated beneficial effects on biomarkers and safety in patients with ischemic HFrEF. However, knowledge gaps remain regarding the safety of oral LT3 therapy in HFrEF. Furthermore, no studies have examined LT3 safety in HFpEF. We intend to fill those gaps through two parallel, randomized, double-blind, placebo-controlled studies of LT3 administration in patients with low T3 syndrome: one in patients with HFrEF and the other in patients with HFpEF. Our safety outcomes will be T3 levels and rhythm monitoring. Our preliminary efficacy outcomes will be peak rate of oxygen consumption (VO2), quality of life, cardiac biomarkers, home activity via actigraphy, and noninvasive assessments of LV function, vascular function, and ventricular-arterial coupling. The proposed studies will assess the safety and preliminary efficacy of administering oral LT3 therapy in two independent study populations. Our team includes a thyroidologist clinical investigator working closely with seasoned HFrEF and HFpEF investigators with extensive early phase trial experience. Strengths of the proposed trials include the controlled design, selection of patients most likely to benefit (those with low T3 levels), careful titration of LT3, and use of clinically relevant outcomes. Conduct of both studies in parallel will enable efficiencies in recruitment and comparisons of safety. The results of these studies will provide essential data to determine if larger scale clinical trials of T3 therapy should be pursued in patients with each condition.